The IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, we discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. We reported in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.[unreadable] [unreadable] Related to IL-21, we previously cloned the IL-21 receptor, generated IL-21 transgenic mice and IL-21R knockout mice, elucidated the mechanism of IL-21 signaling, showed that IL-21 drives the differentiation of Th17 cells (which are important in pathological processes such as Crohn's disease), and critically regulates immunoglobulin production. A range of data also implicated IL-21 as serving a possible role in autoimmunity, particularly in lupus, with elevated IL-21 levels in the BXSB-Yaa mouse model of lupus. Moreover, prior studies from the lab indicated the possible utility of IL-21 as an anti-tumor agent.[unreadable] [unreadable] In the past year, we reported that IL-21 plays a critical role in autoimmune diabetes. The gene encoding IL-21 is near the Idd3 diabetes locus, although these studies indicate that the adjacent IL-2 gene rather than the IL-21 gene that is responsible for this disease susceptiblity locus. Strikingly, when the NOD mouse model when the mice were crossed to the IL-21R knockout background, the mice were devoid of lymphocytic infiltration into the pancreas with prevention of diabetes.[unreadable] [unreadable] Having previously shown anti-tumor potential for IL-21, this past year we showed that IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. IL-21 repressed expression of IL-2Ra an inhibited IL-2-mediated acquisition of a cytolytic CD8+ T cell phenotype. IL-21 did not induce anergy but rather resulted in an increased ability of CD8+ T cells to mediate regression of tumors in vivo after adoptive transfer.[unreadable] [unreadable] We also reported that IL-21 has angiostatic activity, with diminished proliferation and sprouting of activated endothelial cells after treatment with IL-21. This was consistent with the observed presence of receptors for IL-21 on endothelial cells. Importantly, treatment with IL-21 in chick embryos and mouse tumors revealed that IL-21 treatment diminishes vessel outgrowth in vivo. These findings were further supported by the observation that IL-21 causes diminished expression of genes involved in angiogenesis. This effect may well be one mechanism by which IL-21 mediates anti-tumor effects.[unreadable] [unreadable] Overall, our studies help to improve our understanding of signaling by the gc family cytokine IL-21. Our findings clarify molecular mechanisms that are relevant to autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.